A5089871276- Ion channel regulation and function
- Cardiac electrophysiology and arrhythmias
- Neuroscience and Neuropharmacology Research
- Cardiac Ischemia and Reperfusion
- Nanopore and Nanochannel Transport Studies
- Lipid Membrane Structure and Behavior
- Ion Transport and Channel Regulation
- Nicotinic Acetylcholine Receptors Study
- Mass Spectrometry Techniques and Applications
- Fuel Cells and Related Materials
- Neuroscience and Neural Engineering
- Spectroscopy and Quantum Chemical Studies
- Microfluidic and Capillary Electrophoresis Applications
- Ion Channels and Receptors
- Erythrocyte Function and Pathophysiology
- Pancreatic function and diabetes
- Membrane-based Ion Separation Techniques
- Adenosine and Purinergic Signaling
- Ion-surface interactions and analysis
- Receptor Mechanisms and Signaling
- Migraine and Headache Studies
- Coordination Chemistry and Organometallics
- Protein Structure and Dynamics
- Electrochemical Analysis and Applications
- Neuroscience of respiration and sleep
University of Oxford
2016-2025
Boston University
2023
Clarendon College
2009-2021
California Polytechnic State University
2017
Oxfam
2010-2016
Science Oxford
2010-2014
Pfizer (United Kingdom)
2014
Medway School of Pharmacy
2014
University of Kent
2014
Pontificia Universidad Católica de Chile
2010
Adenosine triphosphate (ATP)–sensitive potassium (K ATP ) channels couple electrical activity to cellular metabolism through their inhibition by intracellular ATP. of K varies among tissues and is affected the metabolic regulatory state individual cells, suggesting involvement endogenous factors. It reported here that phosphatidylinositol-4,5-bisphosphate (PIP 2 phosphatidylinositol-4-phosphate (PIP) controlled cloned ir 6.2 SUR1). These phospholipids acted on subunit shifted sensitivity...
A sensitive regulator of cellular potassium class channels called K2P modulates resting membrane potential in most cells. The are regulated by multiple ligands, including the antidepressant drug Prozac, as well factors such mechanical stretch and voltage. Dong et al. determined structure human channel, TREK-2, two conformations bound to a metabolite Prozac. structures show how ligand binding or might induce switching between states. Although both states have open channels, one appears primed...
Two-pore domain (K2P) K(+) channels are major regulators of excitability that endow cells with an outwardly rectifying background "leak" conductance. In some K2P channels, strong voltage-dependent activation has been observed, but the mechanism remains unresolved because they lack a canonical voltage-sensing domain. Here, we show gating is common to most and this voltage sensitivity originates from movement three four ions into high electric field inactive selectivity filter. Overall,...
Abstract THIK-1 ( KCNK13 ) is a halothane-inhibited and anionic-lipid-activated two-pore domain (K2P) K + channel implicated in microglial activation neuroinflammation, current target for the treatment of neurodegenerative disorders, example Alzheimer’s disease amyothropic lateral sclerosis (ALS). However, compared to other K2P channels, little known about structural functional properties THIK-1. Here we present 3.16-Å-resolution cryo-EM structure human that reveals several distinct...
Sulfonylureas stimulate insulin secretion from pancreatic beta-cells by closing ATP-sensitive K+ (K(ATP)). The beta-cell and cardiac muscle K(ATP) channels have recently been cloned shown to possess a common pore-forming subunit (Kir6.2) but different sulfonylurea receptor subunits (SUR1 SUR2A, respectively). We examined the mechanism underlying tissue specificity of sulfonylureas tolbutamide glibenclamide, benzamido-derivative meglitinide, using (Kir6.2/SUR1) (Kir6.2/SUR2A) expressed in...
There has been considerable debate as to whether adenosine triphosphate (ATP) is compartmentalized within cells and, in particular, the ATP concentration directly beneath plasma membrane, experienced by membrane proteins, same that of bulk cytoplasm. This issue difficult address because there no indicator cytosolic ATP, such those available for Ca2+, capable resolving submembrane ([ATP]sm) real time a single cell. We show here mutant ATP-sensitive K+ channels can be used measure [ATP]sm...
Cerebral palsy is a sporadic disorder with multiple likely aetiologies, but frequently considered to be caused by birth asphyxia. Genetic investigations are rarely performed in patients cerebral and there little proven evidence of genetic causes. As part large project investigating children ataxia, we identified four our cohort diagnosis ataxic palsy. They were investigated using either targeted next generation sequencing or trio-based exome found have mutations three different genes, KCNC3,...
The control of ion channel permeation requires the modulation energetic barriers or "gates" within their pores. However, such are often simply identified from physical dimensions pore. Such approaches have worked well in past, but there is now evidence that unusual behavior water narrow hydrophobic pores can produce an barrier to without requiring steric occlusion pathway. Many different channels been shown exploit "hydrophobic gating" regulate flow, and it clear new tools required for more...
Abstract Diabetic peripheral neuropathy (DPN) is a common disabling complication of diabetes. Almost half the patients with DPN develop neuropathic pain (NeuP) for which current analgesic treatments are inadequate. Understanding role genetic variability in development painful needed improved understanding pathogenesis better patient stratification clinical trials and to target therapy more appropriately. Here, we examined relationship between variants voltage-gated sodium channel Na V 1.7...
Recent X-ray crystal structures of the two-pore domain (K2P) family potassium channels have revealed a unique structural architecture at point where cytoplasmic bundle-crossing gate is found in most other tetrameric K(+) channels. However, despite apparently open nature inner pore TWIK-1 (K2P1/KCNK1) structure, reasons underlying its low levels functional activity remain unclear. In this study, we use combination molecular dynamics simulations and validation to demonstrate that possesses...
A key to potassium channel activation Using drugs activate channels has the potential treat conditions like epilepsy, heart arrhythmias, and pain. Schewe et al. report a class of negatively charged activators (NCAs) with defined pharmacore that use similar mechanism many types channels. X-ray crystallography, functional analysis, molecular dynamics simulations showed NCAs bind below selectivity filter open gate Targeting this NCA site might be exploited in rational drug design. Science , issue p. 875
The β cell KATP channel is an octameric complex of four pore-forming subunits (Kir6.2) and regulatory (SUR1). A truncated isoform Kir6.2 (Kir6.2ΔC26), which expresses independently SUR1, shows intrinsic ATP sensitivity, suggesting that this subunit primarily responsible for mediating inhibition. We show here mutation C166, lies at the cytosolic end second transmembrane domain, to serine (C166S) increases open probability Kir6.2ΔC26 approximately sevenfold by reducing time spends in a long...
ATP-sensitive potassium (K ATP ) channels in the pancreatic β cell membrane mediate insulin release response to elevation of plasma glucose levels. They are open at rest but close metabolism, producing a depolarization that stimulates Ca 2+ influx and exocytosis. Metabolic regulation K channel activity currently is believed be mediated by changes intracellular concentrations MgADP, which inhibit activate channel, respectively. The complex four Kir6.2 pore-forming subunits SUR1 regulatory...
We have examined the mechanism by which nucleotides modulate tolbutamide block of β‐cell ATP‐sensitive K + channel (K ATP channel), using wild‐type and mutant channels heterologously expressed in Xenopus oocytes. This is composed sulphonylurea receptor (SUR1) pore‐forming (Kir6.2) subunits. The dose–response relation for currents absence nucleotide showed both a high‐affinity i =2.0 μm) low‐affinity =1.8 mm) site. Kir6.2ΔC36 (a truncated form Kir6.2 independently SUR1) was best fitted with...
The killifish, Fundulus heteroclitus, is a euryhaline teleost fish capable of adapting rapidly to transfer from freshwater (FW) four times seawater (SW). To investigate osmoregulation at molecular level, 5.7-kilobase cDNA homologous human cystic fibrosis transmembrane conductance regulator (hCFTR) was isolated gill library SW-adapted killifish. This encodes protein product (kfCFTR) that 59% identical hCFTR, the most divergent form CFTR characterized date. Expression kfCFTR in Xenopus oocytes...